Novel oxazepinedione-derived symmetric dimers: synthesis and mesophase characterisation of seven-membered heterocyclic compounds

ABSTRACT The synthesis and characterisation of three sets of symmetric dimeric compounds composed of seven-membered oxazepinedione heterocyclic rings were carried out. All the dimers possess the tetradecyl- (n = 14) alkyl side chain attached to the nitrogen atom of the oxazepinedione core. The oxazepinedione core in turn was connected with varied connecting spacers (n = 4, 6, 8, 10 and 12). The dimers were spectroscopically characterised by FT-IR, 1H-NMR, 13C-NMR and elemental analysis techniques. The compounds were investigated for liquid crystalline properties using differential scanning calorimetry and polarising optical microscopy with heating assembly. The precursor imines 2a–e itself started exhibiting liquid crystalline SmA/tilted hexatic mesophase. Further fusion of 2a–e with maleic anhydride, succinic anhydride and phthalic anhydride gave the novel oxazepinedione-derived symmetric dimers 3a–e, 4a–e and 5a–e respectively. The dimers 3a–e and 4a–e did not exhibit any liquid crystal (LC) properties. However, the phthalic anhydride-fused oxazepinediones 5a–e show monotropic nematic liquid crystalline phase. The results indicate that the formation of mesophase is dependent on the type of fused oxazepinedione ring. GRAPHICAL ABSTRACT


Introduction
Dimeric liquid crystals (LCs) exhibit very different behaviour than conventional low molar mass LCs. [1] As a result, these dimers became the focus of considerable research interest due to their unique behaviour as model compounds for polymers. [2] In particular, LC dimers proved to be a rich source of new types of intercalated smectic phases, [3,4] rare and unusual phase transition sequences. More recently, interest has focused on dimers which are derived from the different molecular strategy with various structural and physicochemical parameters. [5] Various terminal and spacer substituents with different alkyl chain lengths can significantly influence the anisotropic properties of LC dimers. The thermal and mesophase behaviours of dimers depend on several factors, such as the structure, type of core, size of the mesogenic units, length of the spacers and terminal groups. [6][7][8] Particularly, LC heterocycles have ability to impart lateral or longitudinal dipole combined with changes in molecular shapes. [9,10] Oxazepines are class of compounds which belong to seven-membered heterocyclic family possessing the nitrogen and oxygen hetero atoms. 1,3-Oxazepine derivatives play an important role in medicinal chemistry since the positions of oxygen and nitrogen in the ring changes the properties of the molecules. [11][12][13][14] The compounds are especially useful as pharmacodynamic agents to suit various applications, especially as anticonvulsant and central nervous system (CNS) depressants. [15][16][17] Very few reports exist in the literature which deals with the LC properties of medium-sized heterocyclic compounds. Five-and six-member heterocyclic rings have been used to attain some LC properties due to the range of structures and known chemistry. These heterocyclic structures show enhanced mesomorphic properties due to their unsaturation or greater polarisability. [18][19][20]  this regard, LC properties of the oxazepine heterocyle have never been investigated because of unfavourable structure for LCs. Recently, we reported the synthesis and characterisation of a large number of 1,3-oxazepinediones as LCs and the investigations have proven to be very beneficial to describe LC properties of 1,3-oxazepinedione core. [21][22][23][24] Before this work, no research had been executed to study the incorporation of mesogenic property into the oxazepine ring. The interest in this class of mesogens is not only because of their ability to act as model compounds for semi-flexible main chain liquid crystalline polymers, but also because of their quite different properties to conventional low molar mass LCs. [25] In order to study the effect of heterocyclic oxazepinedione as a dimer, we now describe the synthesis, characterisation and mesomorphic properties of three novel sets of symmetrical dimers containing 1,3-oxazepinedione core with various spacer lengths.

Synthesis and characterisation
The synthetic approach to the intermediates 2a-e and title oxazepinedione compounds 3a-e, 4a-e and 5a-e is illustrated in Scheme 1. The Schiff base compound 1 was synthesised using condensation reaction between 4-hydroxybenzaldehyde with 4-tetradecylaniline. The intermediates of dimers 2a-e resulted from the Williamson's etherification between compound 1 and various α,ω-dibromoalkanes ranging from C 6 H 12 Br 2 to C 12 H 24 Br 2. [26][27][28] The title compounds 2a-e was subsequently reacted with cyclic anhydrides to yield desired compounds 3a-e, 4a-e and 5a-e.
Recently, we have reported for the first time the reaction of imines with cyclic anhydrides, such as maleic anhydride, succinic anhydride and phthalic anhydride which gave the corresponding seven-member ring as 1,3-oxazepindiones in good yield using dry benzene as solvent. [21,29] Here, we describe the synthesis of dimeric compounds with 1,3-oxazepinedione core using the method described in the literature. [13] The first step involves the synthesis of imine 4-((4tetradecylphenylimino)methyl)phenol (1) from the reaction of 4-tetradecylaniline with 4-hydroxybenzaldehyde in anhydrous ethanol solvent at 80°C for 2 h. The imine 1 was transformed to the 4,4ʹ-(alkyl-1,6diylbis(oxy))bis(4,1-phenylene)bis(methan-1-yl-1-ylidene)bis(4-tetradecylaniline) intermediates 2a-e using corresponding α,ω-dibromoalkanes ranging from C 4 H 9 Br 2 to C 12 H 24 Br 2 by condensation reaction in DMF solvent and CaCO 3 as catalyst. The mixture was refluxed for 4 h at 150°C under continuous stirring. Then, the reaction mixture was poured into 1 L of cold water (approx. 5°C) and the resultant precipitate was filtered. The precipitate was washed once with dilute potassium hydroxide solution (25 mL) and then with water (100 mL). The precipitate was dried and recrystallised from ethanol.
The cyclic anhydrides exhibited good reactivity with the imines. For example, upon refluxing the mixture of intermediate 2a with maleic anhydride gave a white precipitate upon cooling to room temperature in good yield. The compound upon comparison with the compound that we synthesised by a different procedure in the previous study gave the same analytical data. [21] Complete 1 H and 13 C NMR assignments of compounds 3a-e, 4a-e and 5a-e were obtained and substantiated with the aids of DEPT and two-dimensional 1 H-1 H correlation spectroscopy (COSY, NOESY), 1 H-13 C heteronuclear multiple quantum correlation (HMQC) and 1 H-13 C heteronuclear multiple bond correlation (HMBC). Chemical shifts of 1 H and 13 C correlation spectral data which reported in the previous study were used to assign the chemical shifts of the synthesised compounds. [21,29]

Phase transition and mesomorphic behaviours
The phase transition temperatures and corresponding enthalpies of intermediates 2a-e and novel title compounds 3a-e, 4a-e and 5a-e obtained by DSC on first heating and cooling cycle are given in Table 1. The sample was sandwiched between untreated glass plate and a cover slip and subjected to heating and cooling cycles on hot stage at 5°C/min −1 to determine the mesophase textures using polarised optical microscope.
The intermediates 2a-c exhibited monotropic SmA phase and peculiar focal-conic fan-shaped texture depicted in Figure 1(a). Compounds 2d and 2e are reported elsewhere with tilted hexatic mesophase. [30] The mesomorphic temperature ranges for intermediates compounds 2a-e are 17.9°C, 15.1°C, 14.2°C, 16.4°C and 11.5°C, respectively. The DSC thermograms of compounds 2a-e during heating run show only one peak which can be ascribed to the direct isotropisation process (Cr-I). The phase transitions were observed following heating cycle at 178°C, 144°C, 128.6°C, 111.8°C and 94.3°C, respectively. The clearing temperatures decreased with increasing number of carbons in the methylene spacer of 2a-e (Figure 3(a)). This behaviour suggests that increasing the carbon atoms in methylene spacer serves to dilute the core-core interactions when compared with the terminal alkyl chain having n = 14 carbons and this is expected for compounds having high clearing temperatures. Moreover, we believe that increase of terminal alkyl chain evidenced in the formation of smectic A phase, when compared with dimers containing either the ether or ester terminal chains. [31] The imines 2a-e were fused with maleic anhydride to get dimers 3a-e. These compounds hardly exhibited any liquid crystalline properties. Upon heating and cooling processes, all the compounds exhibited subphase [32,33] such as crystal-crystal (Cr 1 -Cr 2 ) and isotropic transitions without showing any LC phase. Upon heating 3a-e dimers, Cr 1 -Cr 2 transitions were observed at 98.5°C, 77.2°C, 94.1°C, 91°C and 80.2°C respectively, and in cooling run, isotropic-Cr 2 transitions were observed at 104.3°C, 122.2°C, 140.2°C, 148°C and 154.3°C, respectively. Further, in compounds 3a-e, it can be generalised that clearing temperatures are found to increase as the length of the flexible spacer chain increases (Figure 3(b)).
Compounds 4a-e were achieved by fusing succinic anhydride with various imines 2a-e. These molecules serve as good examples of homologous dimeric compounds with oxazepandione ring. The only difference between 3a-e and 4a-e is unsaturation to saturation in seven-membered heterocyclic ring. Due to very small change in heterocyclic ring, LC properties are not induced as expected and clearing transitions increased with increasing carbon atoms in the methylene spacer (Figure 3(c)). The transitional properties are very typical indeed with previous studies. [34] Upon heating phase transitions of In order to understand the effective heterocyclic ring to induce mesophase in oxazepandione system, compounds 5a-e with the additional aromatic ring fused to seven-membered ring was also prepared and studied. Compounds 5a and 5b show monotropic nematic phase and compounds 5c-e exhibit monotropic smectic A phase. The DSC thermograms also confirm the formation of liquid crystalline phase for compounds 5a-e. The representative DSC thermogram of 5a is depicted in Figure 2. The DSC thermogram clearly indicates the presence of crystal-crystal transitions in both heating and cooling scans.
While cooling from the isotropic state, compound 5a exhibits nematic phase at 189°C (ΔH = −1.72 kJ mol −1 ) with schlieren texture (Figure 1(b)). The temperature range of nematic phase is 18.7°C. This phenomenon is also observed in compounds 5b, 5c, 5d and 5e at respective temperatures mentioned in Table 1. Interestingly, compounds 5c-e evidenced to form monotropic smectic A phase and it is confirmed from optical microscopy observation for compound 5c (Figure 1   ). The SmA phase range (17.3°C) in compound 5c is wider than SmA and N phase ranges of compounds 5a-d. The transition enthalpies of nematic-isotropic states are rather low for even-membered dimers. This is most likely due to the rather non-linear shape and randomness of the mesogenic units increasing the molecular biaxiality of the compounds. Moreover, in calamitic systems the molecules pack together to maximum utilisation of the space available, and therefore minimise the free volume. The fact that, if a lateral group is attached to the rod the relative N-I clearing point drops considerably. If a flexible chain is attached to the terminus of a rigid rod-like unit, and again a lateral moiety attached to the side of the rod, the fall in the clearing points is similarly very large. [29,30] The plots of temperature dependence with number of carbon atoms in the methylene spacer for 5a-e are shown in Figure 3. The plot indicates that transition temperatures are found to decrease initially, and then smoothly increase as the flexible spacer chain length increases. Overall, the transition temperature observations revealed that the transition temperatures are lower for shorter methyl spacers when compare to the longer methyl spacers.
In our previous studies we had mentioned that all oxazepine rings do not favour the LC property. [21,32] However, we found that the present oxazepine dimeric compounds 5a-e have LC behaviour with enhanced mesophase range when compared to our previous study. Compounds 5a and 5b exhibit nematic phase and compounds 5c-e exhibit smectic phase. The smectic mesophase is favoured in LC dimers with increasing the spacer length. Present series of compounds 5a-e following good agreement with the dimers behaviour reported in the literature. [34][35][36][37][38][39]

Molecular model studies
Molecular model studies have been carried out using HyperChem program to get a better understanding of the relationship between the structure and the type of phases of the molecules. Molecular models of 2c, 3a, 5c and 5e are depicted in Figure 4 (see Supplemental Data) in which the length of methylene spacer varied from n = 4, 6, 8, 10 and 12. Compound 2e favour LC property due to favourable geometry with free volume of the molecular structure. We therefore assign that as a result due to similarity in structure, the whole set of molecules 2a-e exhibit LC property.
In case of compound 3a the molecular structure appears as W-or M-shaped and in this kind of randomness in seven-member heterocyclic molecular geometry it is very hard to favour to pack each other to form any kind of mesophase. As a result, 3a-e and 4ae are non-mesogenic. These novel seven-membered heterocyclics are unable to exhibit mesomorphism presumably because of the incompatibility of the parity within the molecules or the volume fraction mismatch due to rigidity of the oxazepinedione cores.
In the molecular models of 5c and 5e, the structures took random position, the main core is in one plane and oxazepindione heterocycle is taking a different plane. As a result and surprisingly, compounds 5a-e exhibit monotropic LC property. This may be due to low molecular vibration energies allowed for the molecules to assemble each other leading to the LC properties in the cooling scan. We reason that in the nematic phase where the molecules are in thermal motion, fluctuating and gyrating wildly, where opportunities for electrostatic and steric interactions are limited. This is the essence of liquid in the 'liquid crystal', and to think of the molecules being organised into well-ordered arrays where electrostatic interactions are dominant is very unlikely. Rather it is more likely that bulky oxazepindione heterocycle and flexible spacer affect the closeness of intermolecular approach, thereby increasing the free volume, meaning that the formation of the liquid state is easier and hence the clearing point is lower. Thus, the nematic phase is entropically favoured by being orientationally ordered. [30,[40][41][42]

Conclusions
In order to better understand the effect of oxazepindione ring for the formation of mesophases, three series of novel symmetric dimers compose two heterocyclic rings at the core position was synthesised and mesomorphic properties were evaluated. The results indicate the formation of mesophases dependence on the type of oxazepinedione ring. However, the intermediate compounds were found to exhibit monotropic SmA phase on cooling from isotropic phase, while target dimers 3a-e and 4a-e did not exhibit LC property and they exhibit only Cr 1 -Cr 2 upon cooling and heating cycles. Compounds 5a-e were mesogenic on cooling cycle and they exhibit nematic and smectic A phases. The range of nematic phase decreases with increasing the carbon atoms in flexible spacer alkyl chain of compounds 5a-e.

Materials
All the chemicals used are of analytical grade. The chemicals α,ω-dibromoalkanes, 4-hydroxybenzaldehyde, 4-tetradecylaniline, maleic anhydride, succinic anhydride and phthalic anhydride were purchased from Aldrich and used directly from the bottles without further purification. Purity of the compounds were checked by TLC on precoated silica gel on aluminium plates and purified by column chromatography on silica gel (230-400) mesh using 8:2 ratio of ethyl acetate and petroleum benzene as eluent and crystallisation method using appropriate solvents.

Measurement
The elemental (CHN) microanalyses were performed using a Perkin Elmer 2400 LS Series CHNS/O analyser.
The molecular structure of intermediates and title compounds thus obtained were characterised using spectroscopic techniques. The FT-IR spectra were recorded in the range of 4000-400 cm −1 using KBr pellets (Perkin Elmer 2000-FT-IR spectrophotometer). The 1 H and 13 C NMR spectra were recorded in CDCl 3 solvent for 2a-e, and dimethylsulphoxide (DMSO-d 6 ) for 3a-e, 4a-e and 5a-e compounds at 298 K on a Bruker 400 MHz Ultrashied™ FT-NMR spectrometer equipped with a 5 mm BBI inverse gradient probe. Chemical shifts were referenced to internal tetramethylsilane (TMS). The concentration of solute molecules was 50 mg in 1.0 ml DMSO. Standard Bruker pulse programme was used throughout the entire experiment. [43] The transition temperatures and associated enthalpy values were determined using Elmer Pyris 1 differential scanning calorimeter operated at a scanning rate of ± 5°C min −1 on heating and cooling, respectively. Texture observation was carried out using Carl Zeiss Axioskop 40 optical microscope equipped with Linkam LTS350 hot stage and TMS94 temperature controller.
4.3 General synthetic procedure for compounds 3a-e, 4a-e and 5a-e The synthetic method described here is for the compound 3a. The same procedure has been applied for the synthesis of remaining title compounds. Compound 3a was obtained from the reaction of maleic anhydride (0.098 g, 0.001 mol) and 4,4ʹ-(butane-1,6-diylbis(oxy))bis(4,1-phenylene)bis(methan-1-yl-1-ylidene)bis(4-tetradecylaniline) (0.840 g, 0.001 mol) refluxed in CH 3 CN at 80°C for 1 h. The reaction was monitored by TLC and the solvent was distilled off in vacuo. The solid product thus obtained was filtered and purified by column chromatography. The analytical data of FT-IR, 1